Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study previously showed that treatment with telmisartan, an angiotensin II receptor blocker, effectively reduced the transition from incipient to overt nephropathy in Japanese type 2 diabetic patients. However, that large study included both normotensive and hypertensive patients. In the present post hoc analysis, we aimed to assess whether or not telmisartan elicits beneficial effects on the progression of microalbuminuria in normotensive patients. We randomized 163 microalbuminuric (urinary albumin-to-creatinine ratio: UACR of 100 to 300 mg/g creatinine) normotensive type 2 diabetic patients to treatment with telmisartan (40 or 80 mg once daily) or placebo over 52 weeks. The patients treated with either dose of telmisartan showed lower transition rates from microalbuminuria to overt nephropathy compared to the placebo group. In addition, more patients on telmisartan reverted to normoalbuminuria (UACR<30 mg/g creatinine): 15.5% of the 40 mg group, 19.6% of the 80 mg group, and 1.9% of the placebo group. In normotensive patients treated with telmisartan, changes in UACR were not significantly correlated with changes in blood pressure. Side effects did not differ among the groups. The present study demonstrates that telmisartan prevents the progression of microalbuminuria (in some cases induces remission of albuminuria) in normotensive Japanese patients with type 2 diabetes. Telmisartan is shown to be safe and well tolerated in these patients.
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PMID:Microalbuminuria reduction with telmisartan in normotensive and hypertensive Japanese patients with type 2 diabetes: a post-hoc analysis of The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study. 1863 77

An insertion (I)/deletion (D) polymorphism of the angiotensin-converting-enzyme (ACE) gene influences the circulating and renal activity of the renin-angiotensin-aldosterone system. This Practice Point commentary discusses a 2008 paper by Parving et al. that analyzed the interaction between losartan and the I/D polymorphism in patients in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. The investigators found that patients with type 2 diabetes and proteinuria who have the D allele have an unfavorable renal prognosis, which is improved by losartan treatment (vs placebo) when given together with conventional antihypertensive treatment. No significant improvement in outcomes was observed in losartan-treated patients with the II genotype. Previous observational studies had suggested a decreased beneficial effect of ACE inhibitors in patients with type 1 diabetic nephropathy who have the DD genotype. Prospective studies in this area are needed before I/D genotype characterization can be used to guide the choice of therapy in patients with diabetes and proteinuria.
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PMID:ACE gene polymorphism and the prognosis and treatment of overt diabetic nephropathy. 880 48

Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulin-induced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin II-aldosterone systems and their role in glucose metabolism and diabetes prevention.
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PMID:The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. 1885 18

Angiotensin converting enzyme (ACE) generates angiotensin II from angiotensin I, which plays a critical role in the pathophysiology of diabetic nephropathy. However, ACE2 generates angiotensin 1-7, which may protect the kidney by attenuating the effects of angiotensin II, since deletion of the Ace2 gene leads to glomerulosclerosis in mice, and pharmacologic inhibition of ACE2 exacerbates experimental diabetic nephropathy. We measured ACE2 and ACE expression in renal biopsies of patients with kidney disease due to type 2 diabetes to determine if the expression pattern is specific to diabetic nephropathy. ACE2 and ACE mRNA levels were measured by real-time PCR in laser microdissected renal biopsies from 13 diabetic and 8 control patients. ACE2 mRNA was significantly reduced by more than half in both the glomeruli and proximal tubules of the diabetic patients compared to controls, but ACE mRNA was increased in both compartments. There was a significant parallel decrease in ACE2 protein expression, determined by immunohistochemistry, in proximal tubules, a pattern not found in 12 patients with focal glomerulosclerosis or 10 patients with chronic allograft nephropathy. Our results suggest that the kidney disease of patients with type 2 diabetes is associated with a reduction in ACE2 gene and protein expression and this may contribute to the progression of renal injury.
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PMID:Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. 1940 93

Angiotensin-II (Ang-II) exerts many of its vascular effects, including the pathophysiological changes associated with type 2 diabetes, through changes in intracellular calcium concentration [Ca(2+)](i). We sought to clarify the mechanism responsible for Ang-II-induced Ca(2+) influx in cultured aortic VSMC using the Goto-Kakizaki (GK) rat model of type 2 diabetes. Ang-II-induced Ca(2+) influx was blocked by neither VDCC nor c-src inhibition but was sensitive to inositol 1,4,5-trisphosphate receptor inhibition, lanthanide and the diacylglycerol analogue, oleoyl-2-acetyl-sn-glycerol. Since transient receptor potential canonical (TRPC)-3 gene expression was undetectable in both WKY and GK VSMCs and TRPC6 gene and protein expression were significantly down-regulated in GK, we believe the 1/4/5 subgroup of TRPC proteins plays a significant role. Furthermore, in GK VSMC the elevated calcium influx observed was not attributable to increased TRPC expression, but rather an alteration of TRPC activity.
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PMID:Ang-II-induced Ca(2+) influx is mediated by the 1/4/5 subgroup of the transient receptor potential proteins in cultured aortic smooth muscle cells from diabetic Goto-Kakizaki rats. 1913 26

Angiotensin II (Ang II) is well-known as a systemic vasoconstrictor but recently a novel role for the peptide in endocrine function has been suggested and it has been linked to the pathophysiology of type 2 diabetes mellitus. According to several large-scale clinical studies, blocking Ang II prevented the onset of type 2 diabetes in potential patients. Type 2 diabetes is a complicated disease that is primarily characterized by insulin resistance and relative insulin deficiency mediated by numerous organs. Among these organs, the pancreas, adipose tissue, skeletal muscle and liver are the most prominent in maintaining glucose homeostasis. Interestingly, locally generated Ang II has been identified in these organs, where it plays different physiological roles and is produced in relatively high amounts with significant function. In type 2 diabetic human patients or animal models, Ang II, its generating enzymes and receptors are up-regulated and trigger detrimental effects. Moreover, Ang II seems to play roles in the regulation of insulin secretion by the pancreatic beta-cell and insulin sensitivity by peripheral tissues, which are two critical factors contributing to the development of type 2 diabetes. Accordingly, inhibiting Ang II produced beneficial effects on individual organs and throughout the body. Therefore, the present review discusses the role of Ang II in particular organs during normal physiological conditions as well as in type 2 diabetes.
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PMID:Angiotensin II in type 2 diabetes mellitus. 1927 74

The diabetes epidemic continues to grow unabated, with a staggering toll in micro- and macrovascular complications, disability, and death. Diabetes causes a two- to fourfold increase in the risk of cardiovascular disease, and represents the first cause of dialysis treatment both in the UK and the US. Concomitant hypertension doubles total mortality and stroke risk, triples the risk of coronary heart disease and significantly hastens the progression of microvascular complications, including diabetic nephropathy. Therefore, blood pressure reduction is of particular importance in preventing cardiovascular and renal outcomes. Successful antihypertensive treatment will often require a combination therapy, either with separate drugs or with fixed-dose combinations. Angiotensin converting enzyme (ACE) inhibitor plus diuretic combination therapy improves blood pressure control, counterbalances renin-angiotensin system activation due to diuretic therapy and reduces the risk of electrolyte alterations, obtaining at the same time synergistic antiproteinuric effects. ACE inhibitor plus calcium channel blocker provides a significant additive effect on blood pressure reduction, may have favorable metabolic effects and synergistically reduce proteinuria and the rate of decline in glomerular filtration rate, as evidenced by the GUARD trial. Finally, the recently published ACCOMPLISH trial showed that an ACE inhibitor/calcium channel blocker combination may be particularly useful in reducing cardiovascular outcomes in high-risk patients. The present review will focus on different ACE inhibitor combinations in the treatment of patients with type 2 diabetes mellitus and hypertension, in the light of recent clinical trials, including GUARD and ACCOMPLISH.
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PMID:Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials. 1947 78

Aliskiren is the first direct renin inhibitor for the treatment of hypertension. Clinical experience from studies in over 14,000 patients has shown that aliskiren, alone or in combination with other antihypertensive therapies, provides effective blood pressure lowering with a good safety and tolerability profile.The ultimate aim of antihypertensive therapy, however, is to reduce the risk of adverse cardiovascular and renal outcomes.The effect of aliskiren on surrogate markers of organ damage and clinical outcomes is being assessed in the ongoing ASPIRE HIGHER programme, the largest clinical trials programme in the cardio-renal disease area. Results from the ALOFT, AVOID and ALLAY studies suggest that aliskiren has positive effects on markers of cardiovascular and renal damage in patients with type 2 diabetes and nephropathy, heart failure and left ventricular hypertrophy.ASPIRE HIGHER also includes four large-scale studies assessing the potential outcome benefits of aliskiren, and the results of these trials will help define the clinical utility of aliskiren in the treatment of cardiovascular and renal diseases. In this article, we review the antihypertensive efficacy of aliskiren and explore its potential in the management of cardiovascular and renal risk.
J Renin Angiotensin Aldosterone Syst 2009 Jun
PMID:Managing cardiovascular and renal risk: the potential of direct renin inhibition. 1950 53

Impaired kidney function increases the risk of cardiovascular morbidity and mortality. Coexistence of hypertension and type 2 diabetes increases the risk of kidney damage, hypertension being an independent risk factor for kidney disease progression. Angiotensin II, through its inflammatory, proliferative, and thrombotic effects, adversely affects renal perfusion and increases oxidative stress, thus playing a pivotal role in kidney disease progression. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors improve markers of kidney disease and slow kidney disease progression in diabetic and nondiabetic patients; this kidney protection may be in addition to their antihypertensive activity in those with advanced proteinuric nephropathy. Key beneficial effects of ARBs and ACE inhibitors throughout the kidney disease continuum are primarily explained by blood pressure lowering effects and partially by their direct blockade of angiotensin II. Recent studies have shown that telmisartan, an ARB with high lipophilicity and the longest half-life compared with other ARBs, provides benefits on markers of cardiovascular risk, that is, microalbuminuria and slowing of early-stage nephropathy.
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PMID:Effects of angiotensin II receptor blockers on diabetic nephropathy. 1958 50

Elevated blood pressure levels are highly prevalent and are a major reason for cardiovascular events and thus place a significant financial burden on healthcare systems worldwide. Guidelines recommend five first-line anti-hypertensive drug classes, but compelling indications may indicate favoring one drug class over another. Angiotensin receptor blockers (ARBs) have demonstrated a blood pressure lowering efficacy which is at least comparable with other drug classes, including ACE inhibitors (ACE-I), beta-blockers, calcium channel blockers and diuretics. They have, in addition, a lower side effect profile than other drug classes and patients on ARBs are more persistent with therapy. Compelling indications for the use of ARBs are heart failure, post-myocardial infarction, diabetic nephropathy, proteinuria/microalbuminuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and ACE-I induced cough. The ARB irbesartan has demonstrated a high efficacy in lowering blood pressure, which has been shown to be at least comparable with ACE-Is and superior to other ARBs such as losartan and valsartan. This translated into a better cost-effectiveness for irbesartan than for valsartan and losartan in the treatment of hypertension. In addition, irbesartan has been shown to be effective in both early and late stage diabetic nephropathy. It has further demonstrated considerable cost savings over standard therapy including beta-blockers, diuretics and non-dihydropyridine calcium channel blockers at all stages of kidney disease. Based on efficacy data from the Irbesartan Diabetic Nephropathy Trial and Reduction of Endpoints in NIDDM (non insulin dependant diabetes melitis) with the Angiotensin II Antagonist Losartan Study, it has also demonstrated cost savings over losartan in late stage renal disease. While both losartan and irbesartan are registered for the treatment of late stage diabetic nephropathy, irbesartan is also registered for early stage diabetic nephropathy in the EU. In summary, the data from randomized clinical trials on the efficacy of antihypertensive drugs provides an indication of their real value to patients. In addition observational data from clinical practice and proven end-organ protection in diabetic nephropathy provides further evidence of the true value of irbesartan compared to other ARBs in the treatment of hypertension.
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PMID:The value of irbesartan in the management of hypertension. 1960


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